A panel of independent arthritis experts recommended at a March 12, 2012, hearing that the U.S. Food and Drug Administration, or FDA, allow pharmaceutical companies to restart clinical trials of a new class of pain medications known as anti-nerve growth factor agents, or anti-NGFs.

Anti-NGFs are biologic drugs that block nerve growth factor, a protein associated with pain. Clinical trials showed them to have great promise in treating chronic pain from osteoarthritis, or OA, and other causes. But the trials were halted in 2010 after some patients experienced rapid progression of joint damage – specifically, bone death, also called osteonecrosis – requiring total joint replacements.

After reviewing data and receiving comments from drug makers, independent analysts and the public at the hearing, the 21-member panel voted unanimously to allow research to continue on anti-NGFs, provided safety measures are put in place. Ideas recommended by the panel include: testing anti-NGFs alone – not in combination with other medications, such as nonsteroidal anti-inflammatory drugs, or NSAIDs; monitoring patients’ bone health with X-rays and MRIs; and adequately warning trial participants of the potential risks.

The FDA is not obligated to follow the panel’s recommendations, but usually does. If eventually approved, anti-NGFs would be the first biologic drugs to treat OA pain and a variety of other pain conditions including chronic low back pain, diabetic peripheral neuropathy and cancer pain.

Until 2010, three companies had been conducting trials of anti-NGFs. Pfizer was furthest along, with phase 3 studies of its drug tanezumab. Two other companies were in phase 2 trials – Janssen Pharmaceuticals, a Johnson & Johnson company, with fulranumab, and Regeneron with REGN475. The drugs appeared to reduce pain much more effectively than NSAIDs or placebo.

For example, in a 2010 study of 450 knee OA patients, published in the New England Journal of Medicine, or NEJM, and sponsored by Pfizer, patients who received two intravenous administrations of tanezumab eight weeks apart reported 45 to 62 percent less pain, depending on the tanezumab dose – compared with a 22 percent pain reduction among those on placebo.

“The idea [is] that anti-NGFs can block the sensation of pain arising from the joint itself. NSAIDs are anti-inflammatories and may be less effective in people with causes of pain other than inflammation. There are many reasons for joint pain in OA that may not all be inflammatory in nature,” explains Amanda Nelson, MD, a practicing rheumatologist and researcher in OA and epidemiology at the Thurston Arthritis Research Center at the University of North Carolina at Chapel Hill. She has not conducted any research on anti-NGFs, but has helped analyze data from patients with OA as background material for Janssen Pharmaceuticals.

Despite data showing anti-NGFs’ promise for treating pain, in late 2010 and early 2011, the FDA asked the three drug makers to halt research out of safety concerns. Almost 500 joint replacement surgeries were performed among all study participants – raising questions about whether the anti-NGFs were accelerating joint degeneration. The drug makers complied, although trials of anti-NGFs for terminal cancer pain were allowed to continue because the benefits were believed to outweigh the risks for that group.

It’s unclear whether the anti-NGF causes damage and if so, why. One theory is that the pain medication is so effective that people tend to be more active and overuse their damaged joints. “The individual is not able to sense traumatic damage like small fractures due to a lack of sensation, and therefore keeps using the joint, adding to the damage, until it is an end-stage joint requiring joint replacement,” Dr. Nelson explains.

Another possibility is that anti-NGFs affect the blood supply to the joint. “The idea regarding blood supply is that NGF also has a role in the process of angiogenesis, or new blood vessel formation, and somehow by blocking NGF, there is a loss of blood flow to the joint, leading to bone death,” Dr. Nelson says.

At the hearing, each drug company presented an analysis of its study data conducted by its own internal and independent experts. Though their research was at different stages, all the drug makers agree the problems were likely connected to the size of the dose as well as combining the anti-NGFs with NSAIDs.

According to documents submitted by Pfizer to the FDA, “Withdrawals [from the trials] due to adverse events generally increased as a function of the tanezumab dose administered (2.5, 5, or 10 mg) and at any given dose of tanezumab, the addition of an NSAID further increased the incidence of discontinuation due to adverse events.”

All three companies recommended restarting drug trials with the anti-NGFs alone, not in patients also taking NSAIDs. They also proposed limiting the dose and excluding patients with advanced OA.

Nancy E. Lane, MD, a professor of medicine and rheumatology at the University of California, Davis, was one of the authors of the study in NEJM that tested Pfizer’s tanezumab. She applauds the panel’s recommendation to continue with the research.

“The early stages show it can be quite effective, and I think if it’s shown to be safe in additional studies that it will be a useful medication to treat pain for our patients,” she said after the hearing.

Dr. Nelson says it’s good to be cautious about this new class of drug given the seriousness of these complications. But she also believes new treatments for OA pain are badly needed for the roughly 27 million Americans living with the condition. Current pain-control options can be problematic. Long-term use of NSAIDs, like aspirin and ibuprofen, can cause gastrointestinal bleeding and are contraindicated for many patients; opioid analgesics have a long list of side effects, including risk of dependence; and acetaminophen at the recommended doses is often not strong enough.  

“For those people who don’t have other options, [anti-NGFs are] very promising. As a rheumatologist, I see a lot of those folks in my clinic,” Dr. Nelson says. “They can’t have a joint replacement. They can’t tolerate NSAIDs and the other things we have to offer now. In those folks, I think, this has a high degree of promise for alleviating pain and improving quality of life, if the way to use it safely can be identified.”

It isn’t known when – or if – anti-NGFs would become available to the public. At this point, Dr. Nelson says, “The best evidence is still really for weight management, exercise, dietary changes, a healthy lifestyle and those types of interventions. The lifestyle elements are still where most of the evidence is, and are the best things that people can do.”